The immune system reacts to the evolving tumor, so why does it not eradicate tumors? T cell clones that recognize tumor-specific antigens are expanded in cancer patients, yet tumors are rarely spontaneously eradicated by the immune system. Similarly, immune therapies that boost T cells, though showing some efficacy, are inefficient. It appears that the immune response frequently is stymied in the tumor microenvironment. There, T cells are exposed to inhibitory and stimulatory signals, either in the form of soluble or cell-surface derived stimuli. Much is still unclear about how tumor-reactive immune cells function and behave in the microenvironment of naturally evolving tumors. We have literally been blind to the types of dynamic interactions that occur between T cells and antigen presenting, innate immune cells in tumors. However, the nature of the collaboration of the innate and adaptive arms of the immune system can now be fully addressed in situ, within the tumor microenvironment, using mouse models accessible to imaging. Based on preliminary data, we hypothesize that a population of innate immune cells regulate the cells of the adaptive immune system in the microenvironment, protecting the tumor from immune attack. Capitalizing on our ability to concomitantly image innate and adaptive immune cells in situ in mouse models of cancer, we will undertake an assessment of the types of immune cell interactions that occur in the tumor. We will address how interactions between adaptive T cells and innate antigen presenting cells are influenced by microenvironments and by tumor types and how it evolves with tumor progression. We will further seek to identify pathways involved in the collaboration between the innate and adaptive immune responses. Finally, we will use our models to visualize and define what immune and cytotoxic therapy does to the immune response in real-time. In this latter point, direct imaging will guide the development and optimization of therapies. Throughout, we will also coordinate with clinical researchers to undertake concurrent analyses of human biopsy samples to translate our findings into diagnosis and therapy.